According to scientists at the Medical College of Georgia, a particular gene that was previously linked to the formation of fatty deposits in the coronary arteries may hold the key to why many individuals do not respond well to the most common treatment for neovascular age-related macular degeneration (AMD), a major cause of vision loss.
Age-related macular degeneration (AMD) is a condition characterized by abnormal blood vessel growth in the back of the eye. It is commonly found in older individuals and those with diabetes, obesity, and other chronic metabolic diseases. The excessive growth of blood vessels can cause damage to the macula, which is responsible for translating light into image signals.
The first line of defense against AMD is usually anti-VEGF therapy, which works by blocking vascular endothelial growth factor to prevent excessive blood vessel growth.
However, Dr. Yuqing Huo, MD, PhD, the Director of the Center for Pharmacogenomics at Cleveland Clinic, notes that this treatment is only effective for approximately one-third of patients with this form of AMD.
The excess vasculature is often accompanied by the growth of fibroblast cells, according to Dr. Jiefei Huo, the Director of the Vascular Inflammation Program at MCG’s Vascular Biology Center. The proteins produced by these fibroblast cells accumulate outside of the vascular cells, leading to fibrosis or scarring in the eye, which prevents the excess vasculature from being suppressed by anti-VEGF treatments. Huo’s study shows, for the first time, that many fibroblast cells are produced by these excessive endothelial cells. This discovery highlights the need to find a way to prevent this from happening.It is believed that targeting the adenosine receptor 2A (Adora2a) may hold the key. Adora2a is a G-protein-coupled receptor that is present in high levels in the brain, immune cells, and blood vessels. It plays a crucial role in regulating inflammation, myocardial oxygen consumption, and coronary blood flow. Adenosine, a metabolite produced by cells during stress, injury, and oxygen deprivation, can activate Adora2a to protect the body. However, excessive adenosine can lead to abnormal blood vessel growth. In their recent study, Huo and his team discovered a high-level or persistent adenosine-activated Adora2a signal.I can convert endothelial cells, which are the inner cells of the blood vessels, into activated fibroblast cells and ultimately lead to fibrosis. Huo and his team believe that by blocking this receptor, they can prevent this process from occurring.
Using genetically modified mice that develop fibrosis in the backs of their eyes, the researchers administered an Adora2a agonist (KW6002), which attaches to the receptor and stops its function. “We also investigated mice that had Adora2a removed only from the vascular endothelial cells,” says Qiuhua Yang, PhD, a postdoctoral fellow working with Huo and the lead author of this study. ”AllThe research team recently reported that mice with decreased fibrosis in their eyes were a result of the novel findings. These findings were selected as the cover image for Science Translational Medicine.
A postdoctoral fellow in Huo’s lab, Yongfeng Cai, PhD, stated, “We have previously shown that blocking Adora2a can reduce excessive blood vessel growth in the early stages of AMD.” The team is now working on creating an antibody that can recognize Adora2A to further their research. They are considering delivering the antibody through an injection to the back of the eyes, a common approach in eye clinics, to block the activation of Adora2a.Huo and Hong Chen. 2021. A2A adenosine receptor signaling in fibroblasts and macrophages attenuates the inflammatory response and inhibits choroidal neovascularization. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2102252118
Materials provided by University of Pittsburgh Medical Center. Original written by Anita Srikameswaran.
rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnThe researchers discovered that by blocking the Adora2A protein, it could potentially prevent both excessive blood vessel growth, which is a characteristic of the early stage of AMD, and fibrosis, which is a characteristic of the late stage of AMD. This finding suggests that targeting Adora2A may be a more effective treatment option for AMD compared to current treatments. The study was supported by a National Institutes of Health K99 award and funds from the National Eye Institute.
